Molecularly targeted cancer imaging is critical for fundamental improvements in cancer patient care, and image quality and diagnostic accuracy rely heavily on the affinity/specificity between the targeted receptor and targeting ligand (small molecules, peptides and antibodies). A heterodimeric ligand that simultaneously associates two linked ligands with two different targeting receptors provides a broadly applicable approach to convert low affinity ligands (Kdaffinity ~ mM - M) to the one with high avidity/specificity (Kdavidity ~ nM). Such high avidity heterodimers are usually pursued by: 1) synthesizing a number of heterodimers with different linkers; and 2) measuring their in vitro avidities individually. However, once the receptor of interest changes, repeating the entire procedure (including new heterodimer library synthesis and avidity measurement) is required for linker optimization. Even more disappointing is the fact that even by prudently selecting dual-receptor pairs where a potent heterodimer may be applied to a variety of tumors, in a particular lab using particular cell lines(s) where receptor distance(s) varied significantly, heterodimer library synthesis and avidity measurements needs to be conducted again. Therefore, the lack of a generic and rapid linker optimization platform has been considered as one of the major barriers for the widespread and routine utilization of heterodimeric ligand for preclinical and/or clinical studies. In order to overcome this problem, utilizing two bioorthogonal ligations, we propose the first, high-throughput, in vitro screening platform for easy preparation of high avidity heterodimers, which can be broadly applied to various dual-receptor combinations and different tumors. Such widespread applicable technology will significantly accelerate and/or enhance receptor-targeted cancer imaging using heterodimers, particularly in the following situations: 1) when targeted receptor(s) are expressed in low abundance; and 2) situations where no high affinity (and/or specificity) monovalent ligands are available.